Lung cancer is the leading cause of malignancy-related mortality because of its high incidence and the lack of effective treatments. Since tobacco usage contributes to 85-90% of its development, tobacco cessation is the most straightforward strategy for reducing lung cancer incidence and mortality. However, because of the addictive nature of nicotine in tobacco, limited progress has been achieved in reducing tobacco usage. An alternative approach is to block or slow down tobacco carcinogen-induced lung cancer development via chemoprevention (Hecht et al., Nat. Rev. Cancer 2009; 9:476-88). Although a number of compounds have been identified as potential chemopreventive agents against lung tumorigenesis in animal models, their moderate in vivo efficacy leaves ample room for improvement and introduces significant challenges for clinical application/evaluation. In addition, there are very limited successes in cancer chemoprevention relative to cancer therapy.
(+)-Dihydromethysticin can effectively block NNK-induced lung tumorigenesis by reducing NNK-induced DNA damage, with O6-mG being the most carcinogenic damage; this damage can be inhibited by (+)-dihydromethysticin (Leitzman P, et al., Cancer Prevention Research (Philadelphia, Pa.), 2014, 7, 1, 86-96; and Narayanapillai S C, et al., Carcinogenesis, 2014, 35, 10, 2365-72). On the other hand, dihydromethysticin has been reported to activate aryl hydrocarbon receptors that could introduce unwanted biological consequences (Li Y, et al., Toxicological Sciences: an official journal of the Society of Toxicology, 2011, 124, 2, 388-99).
In spite of the above reports there is currently a need for additional agents that are useful for treating or preventing cancer. In particular, there is a need for agents that have fewer side effects than (+)-Dihydromethysticin.